Tobacco use, primarily through cigarette smoking, is the largest cause of preventable mortality in the United States and the world. Other substance addictions cause added public health burdens. The overall objectives of this project are to identify genetic variants that alter risk for smoking and nicotine dependence, and to evaluate their role in determining risk for other substance dependence. In the cholinergic nicotinic receptor subunit gene cluster CHRNA5-CHRNA3-CHRNB4, two distinct groups of nicotine addiction risk variants have now been confirmed in multiple independent studies. Aim 1 will examine these strong genetic findings using genotyped, community-based, longitudinal samples with smoking data. The goal is to determine the broader health implications and epidemiological profile of these risk variants. To further build on the confirmed findings in CHRNA5-CHRNA3-CHRNB4, in Aim 2 we will DNA sequence the larger region of strong linkage disequilibrium containing this cluster in both European-Americans and African-Americans to identify novel genetic variants. We will then genotype and test these variants for association with nicotine dependence in samples from both populations. Aim 3 extends our study of smoking by integrating genotypic and smoking data across several large genome-wide association studies (GWAS). The goal is to identify additional genetic risk variants and gene-gene interactions in this powerful and unique combined sample. In Aim 4 we will examine the relationships between loci identified for smoking and for addiction to other substances. By testing smoking risk loci for association with risk for other substance addiction, we can evaluate the common versus specific effects of these genes on susceptibility to substance dependence. Altogether, this project will further our understanding of the risks conferred by variation in established genes involved in smoking, and will allow us to uncover new genetic loci elsewhere in the genome that contribute to risk for smoking and associated morbidities. PUBLIC HEALTH RELEVANCE: Smoking and nicotine addiction create profound public health burdens. Recent and rapid progress has begun to establish genetic loci that influence risk for smoking. Explaining more of the genetic architecture that underlies this extremely important public health problem will inform continued efforts to prevent and control smoking and other substance addiction.